Bacterial resistance to antibiotics is rising at an alarming rate. Of particular concern is the prevalence of multidrug resistant Gram-negative bacteria (e.g., Pseudomonas aeruginosa), for which all available first-line antibiotics are ineffective. The rate of new drug development is unlikely to keep pace with the increase in multidrug resistance. Consequently, there is a dire need for alternative effective treatment strategies. More toxic agents (e.g., polymyxin B) are used clinically as a last resort. However, formulations of polymyxin B approved for clinical use are available as an unspecified mixture of several structurally related components (e.g., polymyxin B1, B2, B3, etc.);no information is available on the pharmacology and toxicity of individual components. Our long-term goal is to improve the clinical use of polymyxin B to combat the emergence of resistance. The objective of this application is to investigate the pharmacological and toxicity profiles of each of the major polymyxin B component in commercial formulations. If we understand the properties of each of the major polymyxin B component, an improved formulation and / or effective dosing regimens could be developed rationally to provide maximal bacterial killing and minimal drug-induced toxicity. We plan to accomplish the objective of the application by comparing various polymyxin B components with respect to the following: (1) in-vitro and in-vivo potency against clinical multidrug resistant P. aeruginosa;(2) in- vitro and in-vivo nephrotoxicity profiles;and (3) pharmacokinetics in 2 animal infection models. It is our expectation that much-needed information will be generated to improve the treatment of multidrug resistant Gram-negative infections. PUBLIC HEALTH RELEVANCE: As the prevalence of multidrug resistant bacteria increases, many available antibiotics are no longer effective. New effective agents are unlikely to be available in time to solve this crisis. It is critical that we develop alternative treatment strategy and maximize the therapeutic potential of existing agents (e.g., polymyxin B) for multidrug resistant infections. Otherwise, we are at risk of returning to the pre-antibiotic era in the not too distant future.